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Supplementary Material 1

Reasons for exclusion from the review. (DOCX 21Â kb)

Diagnosis and assessment of patients with prostate cancer is dependent on accurate interpretation and grading of histopathology. However, morphology does not necessarily reflect the complex biological changes occurring in prostate cancer disease progression, and current biomarkers have demonstrated limited clinical utility in patient assessment. This study aimed to develop biomarkers that accurately define prostate cancer biology by distinguishing specific pathological features that enable reliable interpretation of pathology for accurate Gleason grading of patients. Online gene expression databases were interrogated and a pathogenic pathway for prostate cancer was identified. The protein expression of key genes in the pathway, including adaptor protein containing a pleckstrin homology (PH) domain, phosphotyrosine-binding (PTB) domain, and leucine zipper motif 1 (Appl1), Sortilin and Syndecan-1, was examined by immunohistochemistry (IHC) in a pilot study of 29 patients with prostate cancer, using monoclonal antibodies designed against unique epitopes. Appl1, Sortilin, and Syndecan-1 expression was first assessed in a tissue microarray cohort of 112 patient samples, demonstrating that the monoclonal antibodies clearly illustrate gland morphologies. To determine the impact of a novel IHC-assisted interpretation (the utility of Appl1, Sortilin, and Syndecan-1 labelling as a panel) of Gleason grading, versus standard haematoxylin and eosin (H&E) Gleason grade assignment, a radical prostatectomy sample cohort comprising 114 patients was assessed. In comparison to H&E, the utility of the biomarker panel reduced subjectivity in interpretation of prostate cancer tissue morphology and improved the reliability of pathology assessment, resulting in Gleason grade redistribution for 41% of patient samples. Importantly, for equivocal IHC-assisted labelling and H&E staining results, the cancer morphology interpretation could be more accurately applied upon re-review of the H&E tissue sections. This study addresses a key issue in the field of prostate cancer pathology by presenting a novel combination of three biomarkers and has the potential to transform clinical pathology practice by standardising the interpretation of the tissue morphology. Refereed/Peer-reviewed

Background: Antiandrogen withdrawal (AAW) response is the paradoxical decrease in prostate-specific antigen (PSA) following the withdrawal of antiandrogen in patients with advanced prostate cancer. Currently, the reported literature on the proportion of patients exhibiting AAW response and the differences in PSA response between the types of antiandrogens is unclear. Methods: This review aimed to explore the PSA response to AAW and to identify if the response depends on the type of antiandrogens. A literature search was performed using databases PubMed, Cochrane and EMBASE with a cut-off date of 23rd of November 2020. Studies reporting on outcomes of AAW and prostate cancer were included. Studies were screened by two reviewers and relevant data extracted. Meta-analysis of outcomes was reported using random-effects and fixed-effects model. A subgroup analysis was performed for type of antiandrogen. Results: From 450 studies, 23 were included with a total of 1474 patients with advanced prostate cancer were available for further analysis. Overall, 395 (26%) patients had any reduction in PSA levels (95% CI: 20–32%) and 183 (11%) patients had a ≥50% reduction in PSA levels (95% CI: 6–16%). Among the 1212 patients on first-generation antiandrogens, 30% (95% CI: 23–38%) had any PSA decline with 15% patients having a ≥50% PSA decline (95% CI: 8–22%). In contrast, among the 108 patients on second-generation antiandrogens, 7% (95% CI: 0–13%) had any PSA decline and only 1% (95% CI: 0–5%) had a ≥50% PSA decline. Also, among the 154 patients on androgen synthesis inhibitors, 26% (95% CI: 19–33%) had any PSA decline and only 4% (95% CI: 0–13%) had a ≥50% PSA decline. Conclusions: One-fourth of patients treated with AAW show a PSA response. However, PSA response to AAW is uncommon with second-generation antiandrogens and androgen synthesis inhibitors. Further research is required to understand the differences in response between the types of antiandrogen. Refereed/Peer-reviewed

Refereed/Peer-reviewed Background and objective: Radical prostatectomy (RP) is a common and widely used treatment for localized prostate cancer. Sequela following RP may include urinary incontinence and sexual dysfunction, outcomes which are recorded within a bi-national Prostate Cancer Outcomes Registry. The objective was to report population-wide urinary incontinence and sexual function outcomes recorded at 12 months following RP; and to quantify and explore factors associated with variation in outcome. Materials and methods The Prostate Cancer Outcomes Registry of Australia and New Zealand (PCOR-ANZ) was used for this study. Participants were treated with radical prostatectomy between 2016 and 2020. Domain summary scores for urinary incontinence and sexual function from the EPIC-26 instrument were the main outcomes, taken at 12 months following surgery (6–18 months). "Major" urinary and sexual function bother were also assessed. Variation in outcomes was investigated using linear and logistic multivariable regression models adjusted for covariates: age, socioeconomic status, PSA at diagnosis, surgical technique, surgical specimen grade group, margin status, and clinician surgical volume. Results and conclusions: The analytic cohort included 13,083 men with the mean urinary incontinence domain score being 76/100 (SD = 25) with 9.2% reporting major bother. For sexual function, the mean score was 29/100 (SD = 26) with 46% reporting major bother. Of the examined variables, age at surgery and surgical volume category were most predictive of function, with disparities exceeding minimally important differences, though large variation was observed between urologists within volume categories. There is considerable variation in 12-month postprostatectomy functional outcomes. Variation is explained by both patient and clinician factors, though some confounders are unmeasured in this cohort.

Purpose The safety of active surveillance (AS) in favorable intermediate-risk (FIR) prostate cancer (PCa) remains uncertain. To provide guidance on clinical decision-making, we examined long-term and pathological outcomes of low-risk and intermediate-risk PCa patients after radical prostatectomy (RP). Methods The study involved 5693 patients diagnosed between 1994 and 2019 with low-risk, FIR, and unfavorable intermediate-risk (UIR) PCa (stratification according to the AUA guidelines) who underwent RP. Pathological outcomes were compared, and Kaplan–Meier analysis determined biochemical recurrence-free survival (BRFS) and cancer-specific survival (CSS) at 5, 10, 15, and 20 years. Multiple Cox regression was used to simultaneously control for relevant confounders. Results Those at FIR had higher rates of upgrading and upstaging (12.8% vs. 7.2%, p 0.001) compared to patients at low risk. The 20-year BRFS was 69%, 65%, and 44% and the 20-year CSS was 98%, 95%, and 89% in low-risk, FIR, and UIR patients. On multiple Cox regression, FIR was not associated with a worse BRFS (HR 1.07, CI 0.87–1.32), UIR was associated with a worse BRFS (HR 1.49, CI 1.20–1.85). Conclusion Patients at FIR had only slightly worse pathological and long-term outcomes compared to patients at low risk, whereas the difference compared to patients at UIR was large. This emphasizes AS in these patients as a possible treatment strategy in well-counseled patients. Supplementary Information The online version contains supplementary material available at 10.1007/s00345-021-03717-2.

Background and purpose: Quality indicators (QIs) have been developed for many aspects of prostate cancer care, but are under-developed with regard to radiotherapy treatment. We aimed to develop a valid, relevant and feasible set of core QIs to measure quality of radiotherapy care in men with prostate cancer. Materials and methods: We used a RAND-modified Delphi process to select QIs that were regarded as both important and feasible measures of quality radiotherapy care. This involved two phases: (1) a literature review to identify a list of proposed QIs; and (2) a QI selection process by an expert panel (n = 12) conducted in a series of three rounds: two online questionnaires’ and one face-to-face meeting. The RAND criterion identified variation in ratings and determined the level of agreement after each round of voting. Results: A total of 144 candidate QIs, which included measures from pre-treatment to post-treatment and survivorship care were identified. After three rounds of voting, the panel approved a comprehensive set of 17 QIs, with most assessing a process of care (n = 16, 94.1%) and the remaining assessing a health outcome. Conclusion: This study developed a core set of 17 QIs which will be used to report from the Prostate Cancer Outcomes Registry-Australia & New Zealand, to monitor the quality of radiotherapy care prostate cancer patients receive. Refereed/Peer-reviewed

Object: To determine the extent and impact of upgrading and downgrading among men who underwent radical prostatectomy (RP) according to new grade groupings and to identify predictors of upgrading from biopsy grade Group I and II, and downgrading to grade Group I, in a community setting. Methods: Study participants included 2279 men with non-metastatic prostate cancer diagnosed 2006–2015 who underwent prostatectomy, from the multi-institutional South Australia Prostate Cancer Clinical Outcomes Collaborative registry. Extent of up- or down-grading was assessed by comparing biopsy and prostatectomy grade groupings. Risk of biochemical recurrence (BCR) with upgrading was assessed using multivariable competing risk regression. Binomial logistic regression was used to identify pre-treatment predictors of upgrading from grade Groups I and II, and risk group reclassification among men with low risk disease. Results: Upgrading occurred in 35% of cases, while downgrading occurred in 13% of cases. Sixty percent with grade Group I disease were upgraded following prostatectomy. Upgrading from grade Group I was associated with greater risk of BCR compared with concordant grading (Hazard ratio: 3.1, 95% confidence interval: 1.7–6.0). Older age, higher prostate-specific antigen levels (PSA), fewer biopsy cores, higher number of positive cores and more recent diagnosis predicted upgrading from grade Group I, while higher PSA and clinical stage predicted upgrading from grade Group II. No clinical risk factors for reclassification were identified. Conclusion: Biopsy sampling errors may play an important role in upgrading from grade Group I. Improved clinical assessment of grade is needed to encourage greater uptake of active surveillance. Keywords: Prostate cancer, Grade misclassification, Biopsy, Radical prostatectomy, Pathology

Background Prostate cancer can be treated with several different modalities, including radiation treatment. Various prognostic tools have been developed to aid decision making by providing estimates of the probability of different outcomes. Such tools have been demonstrated to have better prognostic accuracy than clinical judgment alone. Methods A systematic review was undertaken to identify papers relating to the prediction of clinical outcomes (biochemical failure, metastasis, survival) in patients with prostate cancer who received radiation treatment, with the particular aim of identifying whether published tools are adequately developed, validated, and provide accurate predictions. PubMed and EMBASE were searched from July 2007. Title and abstract screening, full text review, and critical appraisal were conducted by two reviewers. A review protocol was published in advance of commencing literature searches. Results The search strategy resulted in 165 potential articles, of which 72 were selected for full text review and 47 ultimately included. These papers described 66 models which were newly developed and 31 which were external validations of already published predictive tools. The included studies represented a total of 60,457 patients, recruited between 1984 and 2009. Sixty five percent of models were not externally validated, 57% did not report accuracy and 31% included variables which are not readily accessible in existing datasets. Most models (72, 74%) related to external beam radiation therapy with the remainder relating to brachytherapy (alone or in combination with external beam radiation therapy). Conclusions A large number of prognostic models (97) have been described in the recent literature, representing a rapid increase since previous reviews (17 papers, 1966–2007). Most models described were not validated and a third utilised variables which are not readily accessible in existing data collections. Where validation had occurred, it was often limited to data taken from single institutes in the US. While validated and accurate models are available to predict prostate cancer specific mortality following external beam radiation therapy, there is a scarcity of such tools relating to brachytherapy. This review provides an accessible catalogue of predictive tools for current use and which should be prioritised for future validation. Electronic supplementary material The online version of this article (doi:10.1186/s13014-017-0786-z) contains supplementary material, which is available to authorized users.

Objectives: To examine the survival effect of treatment delays from the time of confirmed diagnosis of prostate cancer to first treatment in an Australian population. Methods: Three thousand one hundred and forty patients were identified from the South Australian Prostate Cancer Clinical Outcomes Collaborative database for analysis. Selected patients had dates recorded for both diagnosis and treatment. We examined the effect of treatment delay (the time from diagnosis to date of first treatment) on survival using Cox and competing risks regression and compared quartiles of delay across the cohort. Adjustment was made for age, PSA levels, treatment modality and Gleason score. Outcomes included overall survival (OS) and prostate cancer-specific mortality (PCSM). Results: Quartiles of delay were as follows (days)—Q1: 35, Q2: 86, Q3: 138.0, Q4: 264. Shorter delays were associated with hormonal treatment, high Gleason score and high PSA values. Measuring PCSM with Q2 as reference, age-adjusted associations were—Q1: sHR 4.37 (2.75–6.94), Q3: sHR 1.29 (0.73–2.28), Q4: sHR 1.55 (0.91–2.63). After additional adjustment for treatment type, Gleason score and PSA, Q1 remained at increased risk [sHR 2.46 (1.10–5.54)]. A similar trend was observed for OS. In analysis stratified by Gleason score, delays were not significantly associated with OS. Conclusions: Factors associated with shorter delay in treatment include high Gleason score, high PSA and hormonal treatment. After adjustment for these variables, increased delays were not associated with OS or PCSM in this cohort. The nonlinear association of delay with risk may explain conflicting reports in the literature. Refereed/Peer-reviewed

Background and purpose: To assess the association between PSA velocity (PSAV) in the first 24 months after external beam radiotherapy (EBRT) and prostate cancer-specific mortality (PCSM) and all cause mortality. Conclusion: A rapid decline in PSA in the first year following EBRT is positively associated with PCSM. This may be a useful early indicator of the need for additional therapies. Materials and methods: All eligible patients in the South Australian (SA) Prostate Cancer Clinical Outcomes registry were followed. 848 Patients treated by definitive EBRT with more than one PSA recorded in the two year post-treatment were included. We calculated PSAV by linear regression. Results: The mean number of PSA measurements in the 2 year period was 4.4 (SD1.9). The median PSAVs across quartiles (Q1-Q4) were -4.17, -1.29, -0.38 and 0.20 ng/ml/yr. In multivariable analysis, a U- shaped relationship was seen between PSAV and PCSM with Q1-Q4 hazard ratios (HR) being 3.82 (1.46-10.00), 3.07 (1.10-8.58), 1, 5.15 (1.99-13.30) respectively. HR for all cause mortality in a similar model were 1.79 (1.07-2.98), 1.55 (0.93-2.59), 1.00 and 1.74 (1.04-2.90) for Q1 to Q4 respectively. A rapid PSA decline in the first year was a strong predictor of PCSM. However, in the second year PSA increase was positively associated with PCSM. Refereed/Peer-reviewed

Background: Prostate cancer (PCa) is the most commonly diagnosed malignancy reported to Australian cancer registries with numerous studies from individual registries summarizing diagnostic and treatment characteristics. The aim of this study was to describe annual trends in clinical and treatment characteristics, and changes in surveillance practice within a large combined cohort of men with PCa in South Australia (SA) and Victoria, Australia in 2008-2013. Methods: Common data items from clinical registries in SA and Victoria were merged to develop a cross-jurisdictional dataset consisting of 13,598 men with PCa. Frequencies were used to describe these variables using the National Comprehensive Cancer Network risk of disease progression categories in 10 year age groups. A logistic regression analysis was performed to assess the impact of a number of factors (both individually and together) on the likelihood of men receiving no active treatment within twelve months of the diagnosis (i.e. managed with active surveillance/watchful waiting). Results: Trend analysis showed that over time: (1) men in SA and Victoria are being diagnosed at older age in 2013, 66.1 (SD = 9.7) years compared to 2009 (64.5 (SD = 9.7)); (2) diagnostic methods and characteristics have changed with time; and (3) types of the treatments have changed, with more men having no active treatment. The majority of men were diagnosed with Prostate-Specific Antigen (PSA)

OBJECTIVES: To investigate overall survival and prostate cancer-specific mortality in men with prostate cancer presenting with a PSA level 500 ng/mL. Outcomes measured include overall survival and prostate cancer-specific mortality. Clinical stage, Gleason score and the presence of bony metastasis was evaluated to determine if they were prognostic factors in patients with PSA over 100 at diagnosis. Cox proportional hazards and competing risks regression were used to model overall survival and prostate cancer-specific mortality outcomes respectively.RESULTS: Of this cohort, 241 patients (4.2%) had a diagnostic PSA level >100 ng/mL. Patients with PSA >100 ng/mL have a significant reduction in five (29.1% vs 62.5% vs 87%) and ten-year (18.2% vs 36.7% vs 70.7%) overall survival when compared to men with diagnostic PSA 20-100 and 100 ng/mL at diagnosis. Overall survival at five and ten years was significantly poorer in patients with PSA >100 ng/mL. In this cohort of men presenting with PSA >100 at diagnosis, PSA level was not associated with prostate cancer-specific mortality. Gleason score and metastases are significant prognostic factors in this group of men. Refereed/Peer-reviewed

Background: Prostate cancer is the most commonly diagnosed and prevalent malignancy reported to Australian cancer registries, with numerous studies from single institutions summarizing patient outcomes at individual hospitals or States. In order to provide an overview of patterns of care of men with prostate cancer across multiple institutions in Australia, a specialized dataset was developed. This dataset, containing amalgamated data from South Australian and Victorian prostate cancer registries, is called the South Australian-Victorian Prostate Cancer Health Outcomes Research Dataset (SA-VIC PCHORD). Results: A total of 13,598 de-identified records of men with prostate cancer diagnosed and consented between 2008 and 2013 in South Australia and Victoria were merged into the SA-VIC PCHORD. SA-VIC PCHORD contains detailed information about socio-demographic, diagnostic and treatment characteristics of patients with prostate cancer in South Australia and Victoria. Data from individual registries are available to researchers and can be accessed under individual data access policies in each State. Conclusions: The SA-VIC PCHORD will be used for numerous studies summarizing trends in diagnostic characteristics, survival and patterns of care in men with prostate cancer in Victoria and South Australia. It is expected that in the future the SA-VIC PCHORD will become a principal component of the recently developed bi-national Australian and New Zealand Prostate Cancer Outcomes Registry to collect and report patterns of care and standardised patient reported outcome measures of men nation-wide in Australia and New Zealand. Refereed/Peer-reviewed

Background: The development, monitoring, and reporting of indicator measures that describe standard of care provide the gold standard for assessing quality of care and patient outcomes. Although indicator measures have been reported, little evidence of their use in measuring and benchmarking performance is available. A standard set, defining numerator, denominator, and risk adjustments, will enable global benchmarking of quality of care. Objective: To develop a set of indicators to enable assessment and reporting of quality of care for men with localised prostate cancer (PCa). Design, setting, and participants: Candidate indicators were identified from the literature. An international panel was invited to participate in a modified Delphi process. Teleconferences were held before and after each voting round to provide instruction and to review results. Outcome measurements and statistical analysis: Panellists were asked to rate each proposed indicator on a Likert scale of 1–9 in a two-round iterative process. Calculations required to report on the endorsed indicators were evaluated and modified to reflect the data capture of the Prostate Cancer Outcomes Registry–Australia and New Zealand (PCOR-ANZ). Results and limitations: A total of 97 candidate indicators were identified, of which 12 were endorsed. The set includes indicators covering pre-, intra-, and post-treatment of PCa care, within the limits of the data captured by PCOR-ANZ. Conclusions: The 12 endorsed quality measures enable international benchmarking on the quality of care of men with localised PCa. Reporting on these indicators enhances safety and efficacy of treatment, reduces variation in care, and can improve patient outcomes. Patient summary: PCa has the highest incidence of all cancers in men. Early diagnosis and relatively high survival rates mean issues of quality of care and best possible health outcomes for patients are important. This paper identifies 12 important measurable quality indicators in PCa care. This paper identifies 12 important measurable quality indicators in prostate cancer care. These measures provide a global standard for registries to benchmark quality of care of men with localised prostate cancer Refereed/Peer-reviewed

Androgen deprivation therapy (ADT) can result in a range of adverse symptoms that reduce patients' quality of life. Careful patient counseling on the likely clinical outcomes and adverse effects is therefore vital. The present systematic review was undertaken to identify and characterize all the tools used for the prediction of clinical and patient-reported outcome measures (PROMs) in patients with prostate cancer undergoing ADT. PubMed and EMBASE were systematically searched from 2007 to 2016. Search terms related to the inclusion criteria were: prostate cancer, clinical outcomes, PROMs, ADT, and prognosis. Titles and abstracts were reviewed to find relevant studies, which were advanced to full-text review. The reference lists were screened for additional studies. The Centre for Evidence Based Medicine critical appraisal of prognostic studies tool was applied. The search strategy identified 8755 studies. Of the 8755 studies, 22 on clinical outcomes were identified. However, no studies of PROMs were found. Nine tools could be used to predict clinical outcomes in treatment-naive patients and 10 in patients with recurrence. The Japan Cancer of the Prostate Risk Assessment (J-CAPRA) nomogram was the best performing and validated tool for the prediction of clinical outcomes in treatment-naive patients, and the Chi and Shamash prognostic indexes have been validated for use in patients with castration-resistant disease in different clinical contexts. Using the J-CAPRA nomogram should help clinicians deliver accurate, evidence-based counseling to patients undergoing primary ADT. A strong need exists for primary studies that derive and validate tools for the prediction of PROMs in patients undergoing ADT under any circumstance because these are currently absent from the literature. Refereed/Peer-reviewed

Background: Value-based health care has been proposed as a unifying force to drive improved outcomes and cost containment. Objective: To develop a standard set of multidimensional patient-centered health outcomes for tracking, comparing, and improving localized prostate cancer (PCa) treatment value. Design, setting, and participants: We convened an international working group of patients, registry experts, urologists, and radiation oncologists to review existing data and practices. Outcome measurements and statistical analysisThe group defined a recommended standard set representing who should be tracked, what should be measured and at what time points, and what data are necessary to make meaningful comparisons. Using a modified Delphi method over a series of teleconferences, the group reached consensus for the Standard Set. Results and limitations: We recommend that the Standard Set apply to men with newly diagnosed localized PCa treated with active surveillance, surgery, radiation, or other methods. The Standard Set includes acute toxicities occurring within 6 mo of treatment as well as patient-reported outcomes tracked regularly out to 10 yr. Patient-reported domains of urinary incontinence and irritation, bowel symptoms, sexual symptoms, and hormonal symptoms are included, and the recommended measurement tool is the Expanded Prostate Cancer Index Composite Short Form. Disease control outcomes include overall, cause-specific, metastasis-free, and biochemical relapse-free survival. Baseline clinical, pathologic, and comorbidity information is included to improve the interpretability of comparisons. Conclusions: We have defined a simple, easily implemented set of outcomes that we believe should be measured in all men with localized PCa as a crucial first step in improving the value of care. Patient summary: Measuring, reporting, and comparing identical outcomes across treatments and treatment centers will provide patients and providers with information to make informed treatment decisions. We defined a set of outcomes that we recommend being tracked for every man being treated for localized prostate cancer.